1. Field of the Invention
The present invention relates to vaginal fertility probes and in particular to new probes and associated methods of use. The probes of the present invention provide an electronic device that monitors the endocrinological/physiological status of epithelial tissues in the posterior fornix of the vagina.
More particularly, this invention relates to a probe for predicting and detecting ovulation in mammals, particularly in human females, and to a method of predicting and detecting ovulation that is based solely on the vaginal steady-state measurements of an epithelium-responsive parameter such as alternating current or admittance.
The invention also pertains to a bioassay for pharmacokinetic measurements of hormone replacement therapy in menopausal women, and to the monitoring of other therapies employed in women's health care. The invention also relates to a method and apparatus for women's self-administered health-awareness monitoring.
2. Discussion of the Related Art
U.S. Pat. No. 4,753,247 (Kirsner, Jun. 28, 1988) discloses that measurements of the surface admittance or of the alternating current, performed with non-metallic, and particularly vitreous (or glassy) carbon, electrodes in the posterior fornix of the human vagina, provide a good prediction as well as detection of ovulation. The capability to predict and then detect ovulation was afforded by the therein-presented repeatable cyclic profiles of the probe readings, which exhibited a number of peaks and dips reflecting significant cyclical variations in the recorded parameter.
The cyclic profiles were yielded by the daily probe measurements of the current output from the electrodes that were stimulated by a relatively high-frequency and decidedly low-amplitude alternating voltage. The electrode stimulation was supplied by a small, battery-powered, hand-held apparatus with a digital display for the current output readings. The readings were plotted in a graph against the day of cycle. To the woman-user or to her physician, such a graphical representation of the data would be reminiscent of the graphing of the familiar, if rather unsatisfactory, basal body temperature measurements for fertility assessment.
My '247 patent did not make it clear that, by the time the patent issued, the probe's ovulation-marker minimum had been demonstrated to coincide with the urinary luteinizing hormone (LH) marker of ovulation. W. F. Ganong, “Review of Medical Physiology”, 17th edition, 1995 states that ovulation occurs about 9 hours after the LH surge in blood. The patent only showed that, as expected, the minimum invariably occurred before the rise in the woman's basal body temperature, which is indicative of ovulation having taken place before the temperature rise, consistent with the ovulation-marker minimum.
My 1988 '247 patent noted that the probe's ovulation marker minimum occurs at a time when the vaginal fluids are most conductive. Their increased conductivity is due to the well-known temporary abundance of mucous secretions with high water and salt content at around the time of ovulation. Significantly, the minimum in the probe admittance current is the inverse of that maximal conductivity. My patent made a point about this inverse relationship between the ovulation-marker drop in the probe current and the expected increase in the current that would have to be observed had metal electrodes been employed for conductivity or impedance measurement of the temporarily more conductive cervical mucus secretions.
I now reference examples of such metal electrode devices that yield otherwise featureless vaginal impedance cyclic profiles, exhibiting a simple mid-cycle minimum which is due to the temporarily increased conductivity (i.e., decreased resistance) of the vaginal fluids. This increase in conductivity of vaginal mucus had been published in the sixties and the seventies by farm animal reproduction scientists, and several U.S. patents utilizing that phenomenon were issued in the seventies and the eighties. McDougal, Scott et al. and Lemke (U.S. Pat. Nos. 3,844,276, 4,224,949 and 4,498,481, respectively).
The patents disclosed different electrode configurations, all designed to maximize the contact area with the vaginal fluids for the measurements that were performed with standard ohmmeters. Scott et al. discussed at length the theory of their measurement method and probe. Unlike McDougal and Lemke, they used relatively long rod-shaped electrodes (at least 1 inch and up to 4 inches in length, preferred 2 to 3½ inches). Their ohmmeter could provide AC current at frequency up to 1 MHz (preferred 5 to 100 kHz) and the peak-to-peak voltage between 1 Volt and 10 Volts and preferably between 3 and 6 Volts.
It was not considered in their disclosure that these are very high voltage levels that cause electrode reactions of electrolysis and release of toxic metal ions due to electrode dissolution, which is bound to be harmful to the reproductive tract, particularly at the lower frequencies. While they disclose wide ranges of voltage and frequency, the examples of their cow monitoring results were in fact generated with 3 volts peak-to-peak at 2.5 kHz. They used 3 inch long electrodes that were positioned approximately an inch away from the cervix and the fornix.
One example of the application of this conductometric approach to human fertility monitoring is the Cue Fertility Monitor from Zetek Corporation, which employs a multitude of ring-shaped metal electrodes and is covered by U.S. Pat. No. 4,685,471 (Regas et al., Aug. 31, 1987). Since their vaginal monitor's cyclic profile exhibited only one distinct feature, namely the mid-cycle decrease in vaginal resistance, which afforded no ovulation prediction, Zetek also provided for an additional separate measurement of the conductivity of saliva. Salivary resistance gave no indication of ovulation but it did give them a long-term predictive signal about a week before ovulation. While such a long-term predictive signal is of great potential significance, neither the oral nor more importantly the vaginal measurements with the Zetek Cue Fertility Monitor generated any short-term predictive signal such as is produced by the probe disclosed in my '247 patent. The Cue's vaginal resistance cyclic profile is also devoid of the other multiple features that were described in my prior art patent.
The other example is a very similar, even if somewhat simplified, vaginal probe device and technique akin to the Cue and disclosed in U.S. Pat. No. 5,240,010 (Weinmann, Aug. 31, 1993). The patent purports to solve the problem of absent predictive signals by the introduction of the fundamentally wrong and therefore discredited rhythm-method calculation into the software of the device. Weinmann's recourse to the rhythm method is illogical because had the rhythm method worked, there would be no need to obviate its use with new technological tools. In his patent, Weinmann refers to but does not describe his software as evaluating the same profile of vaginal impedance as the profile generated by the Zetek Cue Monitor; the undisclosed software would additionally utilize a temperature-rise signal to define the end of the fertile period.
Note that no similar recourse, to either an additional oral measurement or to a 15 rhythm method calculation or to a temperature measurement, has been necessary with my probe technology as disclosed in the '247 patent.
My '247 patent was based on the assumption that only the special vitreous (or glassy) carbon electrodes were able to perform the vaginal measurements in the claimed manner. The assumption was that only the glassy carbon electrodes (gce) would yield the unprecedented cyclic profiles with the distinct and multiple features that provide the most important capability to predict as well as to detect ovulation. At the time and until recently, I was convinced that, in addition to the importance of performing the measurements in the posterior fornix of the vagina, my probe measured greater variations during the menstrual cycle than any other vaginal monitoring technique because of my particular method of measurement (namely, admittance or alternating current response to a.c.-applied small potential difference of relatively high frequency), performed with the particular kind of electrode material that I used and patented.
I held that view for several reasons: a) because no other vaginal monitor yielded any multi-featured cyclic profile (and they all used electrode materials other than vitreous carbon): b) because the vitreous carbon was undoubtedly biocompatible and novel in the gynecological diagnostic application; c) because, in my opinion, the vitreous carbon electrode is electrochemically distinct from metal electrodes and from electrodes made of other forms of carbon such as graphite or carbon paste; and d) because I was a practitioner of modern bioelectrochemistry and its electrodic (as opposed to ionic) and fuel-cell concepts of physiological phenomena. In these concepts, the classical (equilibrium) Nernst equation and ionic mechanisms are replaced with the Butler-Volmer and/or Tafel (kinetic) formalization of electrodic measurements and mechanisms.
In brief, at the inception of the project I envisaged the epithelium of the posterior fornix to function in a manner similar to the membrane models later rationalized in academic literature (e.g., Electrochim. Acta, 34, 567, 1989; J. Biol. Phys. 14, 31, 1986; J. Bioelectrochem. 3, 247, 1984), basically as a network of microscopic biochemical fuel cells. My 247 patent gave an example of a conceivable redox reaction involved in the hypothetical electron transfer network, and stated that “while not wishing to be bound by theory, the present inventor believes that this is an example of many such reactions”.
In the present application, I continue to maintain the position of not being bound by theory. However, I would add an important characteristic to my conceptual electrodic network, namely the susceptibility of some of the network components to at least some of the sex hormones and/or other chemicals involved in fertility cycling. A general example of such hormone-responsive electrodic components could be the enzymes that drive the cyclical changes in the composition of the epithelial cells and in the mucus secretions of the epithelia. Such enzymes could respond to the hormones by means of associated hormone-receptor sites. The genital tract is, in fact, known to be rich in the concentrations of the sex hormone receptors. Note that the classical concepts of ionics do not lend themselves to such responsiveness to hormones and other modulators. For more insight, the 1993 book “Surface Electrochemistry. A Molecular Level Approach” provides an eloquent account of the concepts and principles, including those of bioelectrochemistry, that inspired the design of the original Kirsner vaginal probe as a tool for scientific family planning.